Delineating vulnerability to episodes of major depressive disorder (MDD) is important for designing and targeting preventive interventions. We are thus examining non-depressed adult people at high risk for depression and prospectively following for the incidence of an MDD episode. In particular, we are currently focusing on patients who have been prescribed interferon-alpha (IFN-a) for hepatitis C. Among patients not currently depressed, about 25% have elevated vulnerability and develop an MDD episode during subsequent IFN- a therapy. We have discovered that a major marker of vulnerability, observed prior to starting IFN- a, is poor self-reported sleep quality. Notably, poor sleep quality's relationship with vulnerability was independent from any other self-reported concurrent depression symptoms. Because delta (or 'slow wave') sleep has been associated with restorative processes in the brain, and low levels have been cross-sectionally observed during depression or insomnia, we hypothesize that low delta sleep power in non-depressed people is related to vulnerability for subsequent MDD. We will test this hypothesis by using polysomnography and power spectral analysis to examine non-depressed people before they start IFN- a. Well-characterized subjects will then be prospectively followed during treatment. Concurrently, we will examine potential influences on the sleep quality/MDD vulnerability relationship. One likely influence is interleukin-6 (IL-6), whose elevated daytime levels prior to treatment are associated with both worsening depression and sleep during IFN- a therapy. It is plausible that glucocorticoid resistance may lead to flattening of the circadian IL-6 rhythm, increased daytime levels, and impaired sleep regulation. Secondly, we and others have observed that promoter polymorphisms in the serotonin transporter may be associated with poor sleep quality, plausibly mediating their relationship to MDD. We also have preliminary evidence for other related genetic polymorphisms that may influence depression vulnerability via their effects on sleep. Our careful clinical assessment of the longitudinal relationships among depression, sleep, inflammatory cytokines, and genetic vulnerability in people receiving IFN- a could lead to novel targeted strategies for prevention of depression in the millions of people with hepatitis C, and could have broader relevance to depression prevention more generally. This high-impact agenda for this re-submission (MH090250-01-A1) coincides with the 2008 NIMH strategic plan to determine the biologic bases leading to MDD.